The present invention relates to quinoline compounds, to methods of using such compounds in treating cGMP-associated conditions such as erectile dysfunction, and to pharmaceutical compositions containing such compounds.
Erectile dysfunction is the inability to obtain and maintain a penile erection sufficient for sexual intercourse or other sexual expression. A number of factors can place an individual at risk for this disorder, for example, trauma, pelvic surgery, hypercholesterolemia, ischemic heart disease, peripheral vascular disease, chronic renal failure, diabetes, the use of certain medicaments including some types of antihypertensive agents, digoxin, or the excessive use of narcotics, alcohol, tobacco, etc. Methods for treating erectile dysfunction include the use of vacuum devices and penile implants, as well as the administration of medicaments such as yohimbine, papaverine and apomorphine. Improved methods for treating this disorder are sought, however, as the aforementioned methods do not provide sufficient efficacy and/or are accompanied by drawbacks or side effects such as erosion, pain, priapism, or gastrointestinal discomfort.
A penile erection is dependent upon the presence of adequate levels of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP), especially in corpora cavernosa tissue. Thus, administering an inhibitor of a cGMP phosphodiesterase (cGMP PDE), particularly a selective inhibitor of cGMP PDE Type 5 (PDE 5), provides a means for achieving and maintaining an erection and therefore, for treating erectile dysfunction. See Trigo-Rocha et al., xe2x80x9cNitric Oxide and cGMP: Mediators of Pelvic Nerve-Stimulated Erection in Dogs,xe2x80x9d Am. J. Physiol., Vol. 264 (February 1993); Bowman et al., xe2x80x9cCyclic GMP Mediates Neurogenic Relaxation in the Bovine Retractor Penis Muscle,xe2x80x9d Br. J. Pharmac., 81, 665-674 (1984); and Rajfer et al, xe2x80x9cNitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission,xe2x80x9d New England J. Med., 326, 2, 90-94 (January 1992). Sildenafil, for example, has been described as a PDE 5 inhibitor useful for treating erectile dysfunction. See Drugs of the Future, 22, 138-143 (1997).
Recent examples of other compounds claimed as PDE 5 inhibitors include fused pyridazine compounds (WO 96/05176 and U.S. patent application Ser. No. 09/393,833), anthranilic acid derivatives (U.S. Pat. No. 5,716,993), fused pyridopyridazine compounds (U.S. patent application Ser. No. 09/526,162), and quinazolinone compounds (U.S. Pat. No. 6,087,368).
The present invention provides compounds that are potent and selective inhibitors of cGMP PDE 5. These compounds may be employed in treating erectile dysfunction. In view of their activity, these compounds can also be used in treating other disorders responding to the inhibition of cGMP PDE, such as various cardiovascular disorders.
The present invention provides quinoline compounds of the following formula (I) or salts thereof, for use as inhibitors of cGMP PDE, especially Type 5: 
wherein:
R2, R6, R7 and R8 are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, or heterocyclo;
R3 is xe2x80x94(CH2)zY, wherein z is 0, 1, 2, or 3;
R4 and R5 (i) are independently hydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the proviso that R4 and R5 are not both hydrogen; or (ii) taken together form a heterocyclo ring;
Y is selected (i) independently from xe2x80x94OR9, xe2x80x94CO2R9, xe2x80x94CH(CO2R9)2, xe2x80x94O(Cxe2x95x90O)NR10R11, xe2x80x94NR10R11, xe2x80x94NR10(Cxe2x95x90O)NR11R12, xe2x80x94CH[(Cxe2x95x90O)NR10R11]2, xe2x80x94(Cxe2x95x90O)NR10R11, xe2x80x94NR10(Cxe2x95x90O)R12, xe2x80x94S(O)mR9, xe2x80x94SO2NR10R11, imidazole, substituted imidazole, triazole, substituted triazole, or cyano, or (ii) together with one of R4and R5 to form a heterocylo ring therewith;
m is 0, 1, or 2;
R9 is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl; and
R10, R11, and R12 (i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl; or (ii) taken together wherein R10 forms a three- to seven-membered heterocyclo ring with R11 or R12, or R11 forms a three- to seven-membered heterocyclo ring with R12.
The invention further provides pharmaceutical compositions adapted for use in treating cGMP-associated conditions comprising a pharmaceutically acceptable diluent or carrier and at least one compound of the formula (I) or salt thereof, wherein R2 and R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined above and R3 is selected from hydrogen and xe2x80x94(CH2)zY, with the proviso that at least one of R2, R3, R6, R7, and R8 is not hydrogen. The invention further provides methods for treating cGMP-associated conditions comprising administering to a mammal in need of such treatment a therapeutically-effective amount of one or more compounds of the formula (I) or salt thereof, wherein R2 and R4, R5, R6, R7, R8, R9, R10, R11 and R12are as defined above and R3 is selected from hydrogen and xe2x80x94(CH2)zY, with the proviso that at least one of R2, R3, R6, R7, and R8 is not hydrogen.